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1.  Association of Non-alcoholic Fatty Liver Disease with Chronic Kidney Disease: A Systematic Review and Meta-analysis 
PLoS Medicine  2014;11(7):e1001680.
In a systematic review and meta-analysis, Giovanni Musso and colleagues examine the association between non-alcoholic fatty liver disease and chronic kidney disease.
Please see later in the article for the Editors' Summary
Background
Chronic kidney disease (CKD) is a frequent, under-recognized condition and a risk factor for renal failure and cardiovascular disease. Increasing evidence connects non-alcoholic fatty liver disease (NAFLD) to CKD. We conducted a meta-analysis to determine whether the presence and severity of NAFLD are associated with the presence and severity of CKD.
Methods and Findings
English and non-English articles from international online databases from 1980 through January 31, 2014 were searched. Observational studies assessing NAFLD by histology, imaging, or biochemistry and defining CKD as either estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m2 or proteinuria were included. Two reviewers extracted studies independently and in duplicate. Individual participant data (IPD) were solicited from all selected studies. Studies providing IPD were combined with studies providing only aggregate data with the two-stage method. Main outcomes were pooled using random-effects models. Sensitivity and subgroup analyses were used to explore sources of heterogeneity and the effect of potential confounders. The influences of age, whole-body/abdominal obesity, homeostasis model of insulin resistance (HOMA-IR), and duration of follow-up on effect estimates were assessed by meta-regression. Thirty-three studies (63,902 participants, 16 population-based and 17 hospital-based, 20 cross-sectional, and 13 longitudinal) were included. For 20 studies (61% of included studies, 11 cross-sectional and nine longitudinal, 29,282 participants), we obtained IPD. NAFLD was associated with an increased risk of prevalent (odds ratio [OR] 2.12, 95% CI 1.69–2.66) and incident (hazard ratio [HR] 1.79, 95% CI 1.65–1.95) CKD. Non-alcoholic steatohepatitis (NASH) was associated with a higher prevalence (OR 2.53, 95% CI 1.58–4.05) and incidence (HR 2.12, 95% CI 1.42–3.17) of CKD than simple steatosis. Advanced fibrosis was associated with a higher prevalence (OR 5.20, 95% CI 3.14–8.61) and incidence (HR 3.29, 95% CI 2.30–4.71) of CKD than non-advanced fibrosis. In all analyses, the magnitude and direction of effects remained unaffected by diabetes status, after adjustment for other risk factors, and in other subgroup and meta-regression analyses. In cross-sectional and longitudinal studies, the severity of NAFLD was positively associated with CKD stages. Limitations of analysis are the relatively small size of studies utilizing liver histology and the suboptimal sensitivity of ultrasound and biochemistry for NAFLD detection in population-based studies.
Conclusion
The presence and severity of NAFLD are associated with an increased risk and severity of CKD.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Chronic kidney disease (CKD)—the gradual loss of kidney function—is becoming increasingly common. In the US, for example, more than 10% of the adult population (about 26 million people) and more than 25% of individuals older than 65 years have CKD. Throughout life, the kidneys perform the essential task of filtering waste products (from the normal breakdown of tissues and from food) and excess water from the blood to make urine. CKD gradually destroys the kidneys' filtration units, the rate of blood filtration decreases, and dangerous amounts of waste products build up in the blood. Symptoms of CKD, which rarely occur until the disease is very advanced, include tiredness, swollen feet, and frequent urination, particularly at night. There is no cure for CKD, but progression of the disease can be slowed by controlling high blood pressure and diabetes (two risk factors for CKD), and by adopting a healthy lifestyle. The same interventions also reduce the chances of CKD developing in the first place.
Why Was This Study Done?
CKD is associated with an increased risk of end-stage renal (kidney) disease and of cardiovascular disease. These life-threatening complications are potentially preventable through early identification and treatment of CKD. Because early recognition of CKD has the potential to reduce its health-related burden, the search is on for new modifiable risk factors for CKD. One possible new risk factor is non-alcoholic fatty liver disease (NAFLD), which, like CKD is becoming increasingly common. Healthy livers contain little or no fat but, in the US, 30% of the general adult population and up to 70% of patients who are obese or have diabetes have some degree of NAFLD, which ranges in severity from simple fatty liver (steatosis), through non-alcoholic steatohepatitis (NASH), to NASH with fibrosis (scarring of the liver) and finally cirrhosis (extensive scarring). In this systematic review and meta-analysis, the researchers investigate whether NAFLD is a risk factor for CKD by looking for an association between the two conditions. A systematic review identifies all the research on a given topic using predefined criteria, meta-analysis uses statistical methods to combine the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 33 studies that assessed NAFLD and CKD in nearly 64,000 participants, including 20 cross-sectional studies in which participants were assessed for NAFLD and CKD at a single time point and 13 longitudinal studies in which participants were assessed for NAFLD and then followed up to see whether they subsequently developed CKD. Meta-analysis of the data from the cross-sectional studies indicated that NAFLD was associated with a 2-fold increased risk of prevalent (pre-existing) CKD (an odds ratio [OR]of 2.12; an OR indicates the chance that an outcome will occur given a particular exposure, compared to the chance of the outcome occurring in the absence of that exposure). Meta-analysis of data from the longitudinal studies indicated that NAFLD was associated with a nearly 2-fold increased risk of incident (new) CKD (a hazard ratio [HR] of 1.79; an HR indicates often a particular event happens in one group compared to how often it happens in another group, over time). NASH was associated with a higher prevalence and incidence of CKD than simple steatosis. Similarly, advanced fibrosis was associated with a higher prevalence and incidence of CKD than non-advanced fibrosis.
What Do These Findings Mean?
These findings suggest that NAFLD is associated with an increased prevalence and incidence of CKD and that increased severity of liver disease is associated with an increased risk and severity of CKD. Because these associations persist after allowing for established risk factors for CKD, these findings identify NAFLD as an independent CKD risk factor. Certain aspects of the studies included in this meta-analysis (for example, only a few studies used biopsies to diagnose NAFLD; most used less sensitive tests that may have misclassified some individuals with NAFLD as normal) and the methods used in the meta-analysis may limit the accuracy of these findings. Nevertheless, these findings suggest that individuals with NAFLD should be screened for CKD even in the absence of other risk factors for the disease, and that better treatment of NAFLD may help to prevent CKD.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001680.
The US National Kidney and Urologic Diseases Information Clearinghouse provides information about all aspects of kidney disease; the US National Digestive Diseases Information Clearinghouse provides information about non-alcoholic liver disease
The US National Kidney Disease Education Program provides resources to help improve the understanding, detection, and management of kidney disease (in English and Spanish)
The UK National Health Service Choices website provides information for patients on chronic kidney disease, including some personal stories, and information on non-alcoholic fatty liver disease
The US National Kidney Foundation, a not-for-profit organization, provides information about chronic kidney disease (in English and Spanish)
The not-for-profit UK National Kidney Federation provides support and information for patients with kidney disease and for their carers
The British Liver Trust, a not-for-profit organization, provides information about non-alcoholic fatty liver disease, including a patient story
doi:10.1371/journal.pmed.1001680
PMCID: PMC4106719  PMID: 25050550
2.  Renal Function and Risk of Coronary Heart Disease in General Populations: New Prospective Study and Systematic Review 
PLoS Medicine  2007;4(9):e270.
Background
End-stage chronic kidney disease is associated with striking excesses of cardiovascular mortality, but it is uncertain to what extent renal function is related to risk of subsequent coronary heart disease (CHD) in apparently healthy adults. This study aims to quantify the association of markers of renal function with CHD risk in essentially general populations.
Methods and Findings
Estimated glomerular filtration rate (eGFR) was calculated using standard prediction equations based on serum creatinine measurements made in 2,007 patients diagnosed with nonfatal myocardial infarction or coronary death during follow-up and in 3,869 people without CHD in the Reykjavik population-based cohort of 18,569 individuals. There were small and nonsignificant odds ratios (ORs) for CHD risk over most of the range in eGFR, except in the lowest category of the lowest fifth (corresponding to values of <60 ml/min/1.73m2), in which the OR was 1.33 (95% confidence interval 1.01–1.75) after adjustment for several established cardiovascular risk factors. Findings from the Reykjavik study were reinforced by a meta-analysis of six previous reports (identified in electronic and other databases) involving a total of 4,720 incident CHD cases (including Reykjavik), which yielded a combined risk ratio of 1.41 (95% confidence interval 1.19–1.68) in individuals with baseline eGFR less than 60 ml/min/1.73m2 compared with those with higher values.
Conclusions
Although there are no strong associations between lower-than-average eGFR and CHD risk in apparently healthy adults over most of the range in renal function, there may be a moderate increase in CHD risk associated with very low eGFR (i.e., renal dysfunction) in the general population. These findings could have implications for the further understanding of CHD and targeting cardioprotective interventions.
John Danesh and colleagues conclude there may be a moderate increase in risk of coronary heart disease associated with very low estimated glomerular filtration rate.
Editors' Summary
Background.
Coronary heart disease (CHD), the leading cause of death in most Western countries, is a “cardiovascular” disease—literally a disorder affecting the heart and/or blood vessels. In CHD, the blood vessels that supply the heart become increasingly narrow. Eventually, the flow of blood to the heart slows or stops, causing chest pains (angina), breathlessness, and heart attacks. Many factors increase the risk of developing CHD and other cardiovascular diseases, including high blood pressure, high blood levels of cholesterol (a type of fat), or being overweight. Individuals can reduce their chances of developing cardiovascular disease by taking drugs to reduce their blood pressure or cholesterol levels or by making lifestyle changes (so-called cardioprotective interventions). Another important risk factor for cardiovascular disease is end-stage chronic kidney disease (CKD), a condition in which the kidneys stop working. (In healthy people, the kidneys remove waste products and excess fluid from the body.) People with end-stage CKD (which is treated by dialysis) have about a five times higher risk of dying from cardiovascular disease compared with healthy people.
Why Was This Study Done?
End-stage CKD is preceded by a gradual loss of kidney function. There is a clear association between non-dialysis–dependent CKD and the incidence of cardiovascular events (such as heart attacks) in people who already have signs of cardiovascular disease. But are people with slightly dysfunctional kidneys (often because of increasing age) but without any obvious cardiovascular disease at greater risk of developing cardiovascular diseases than people with fully functional kidneys? If the answer is yes, it might be possible to reduce CHD deaths by minimizing the exposure of people with CKD to other risk factors for cardiovascular disease. In this study, the researchers have taken two approaches to answer this question. In a population-based study, they have examined whether there is any association in healthy adults between kidney function measured at the start of the study and incident CHD (the first occurrence of CHD) over subsequent years. In addition, they have systematically searched the published literature for similar studies and combined the results of these studies using statistical methods, a so-called “meta-analysis.”
What Did the Researchers Do and Find?
Between 1967 and 1991, nearly 19,000 middle-aged men and women without a history of heart attacks living in Reykjavik, Iceland, enrolled in a prospective study of cardiovascular disease. Baseline blood samples were taken at enrollment and the participants' health monitored for 20 years on average. The researchers identified 2,007 participants who suffered a nonfatal heart attack or died of CHD during follow-up and 3,869 who remained disease free. They then calculated the estimated glomerular filtration rate (eGFR; a measure of kidney function) for each participant from baseline creatinine measurements (creatinine is a muscle waste product). There was no association between lower-than-average eGFRs and the risk of developing CHD over most of the range of eGFR values. However, people whose eGFR was below approximately 60 units had about a 40% higher risk of developing CHD after allowing for established cardiovascular risk factors than individuals with higher eGFRs. This finding was confirmed by the meta-analysis of six previous studies, which included a further 2,700 incident CHD cases.
What Do These Findings Mean?
These findings indicate that people with an eGFR below about 60 units (the cut-off used to define CKD) may have an increased risk of developing CHD. They also indicate a nonliner association between kidney function and CHD risk. That is, any association with CHD became evident only when the eGFR dropped below about 60 units. These findings need confirming in different ethnic groups and by using more accurate methods to measure eGFRs. Nevertheless, they suggest that improving kidney function across the board is unlikely to have much effect on the overall incidence of CHD. Instead, they suggest that targeting cardioprotective interventions at the one in ten adults in Western countries whose eGFR is below 60 units might be a good way to reduce the burden of CHD.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040270.
MedlinePlus encyclopedia pages on coronary heart disease, chronic kidney failure, and end-stage kidney disease (in English and Spanish).
Information for patients and carers from the American Heart Association on all aspects of heart disease, including prevention of CHD
Information from the British Heart Foundation on heart disease and on keeping the heart healthy
Information on chronic kidney disease from the US National Kidney Foundation, and the US National Kidney and Urologic Diseases Information Clearing House (in English and Spanish)
Information on chronic kidney disease from the UK National Kidney Foundation
doi:10.1371/journal.pmed.0040270
PMCID: PMC1961630  PMID: 17803353
3.  Prevalence, determinants and co-morbidities of chronic kidney disease among First Nations adults with diabetes: results from the CIRCLE study 
BMC Nephrology  2012;13:57.
Background
Indigenous peoples worldwide are experiencing elevated rates of type 2 diabetes and its complications. To better understand the disproportionate burden of diabetic end stage renal disease (ESRD) among Canadian First Nations people (FN), we examined prevalence, determinants, and co-morbidities of chronic kidney disease (CKD) within this population.
Methods
The 2007 Canadian FN Diabetes Clinical Management and Epidemiologic (CIRCLE) study conducted a cross-sectional national medical chart audit of 885 FN adults with type 2 diabetes to assess quality of diabetes care. In this sub-study, participants were divided by estimated glomerular filtration rate (eGFR in ml/min/1.73 m2), as well as by albuminuria level in those with eGFRs = > 60. Those with eGFRs = > 60 and negative albuminuria were considered to have normal/near normal kidney function (non-CKD). Using univariate and logistic regression analysis, they were compared with participants having eGFRs = > 60 plus albuminuria (CKD-alb) and with participants having eGFRs <60 (CKD-eGFR <60).
Results
While 84.5% of total CIRCLE participants had eGFRs = > 60, almost 60% of the latter had CKD-alb. Of the 15.5% of total participants with CKD-eGFR <60, 80% had eGFRs 30–60 (Stage 3 CKD) but over 10% (1.6% of total participants) had ESRD. Independent determinants of CKD-alb were male gender and increasing diabetes duration, systolic BP, A1C and total cholesterol. These plus smoking rates also discriminated between FN with micro- and macro-albuminuria. Independent determinants of CKD-eGFR <60 were increasing age at diabetes diagnosis, diabetes duration, total cholesterol and systolic BP. However, participants with CKD-eGFR <60 also displayed a decreasing mean age of diabetes diagnosis as eGFR declined. Micro-vascular co-morbidities were significantly associated with CKD-alb but both micro- and macro-vascular co-morbidities were associated with CKD-eGFR <60. Only 35-40% of participants with CKD used insulin.
Conclusions
High prevalences of CKD-alb and early CKD-eGFR <60 among diabetic FN were largely related to modifiable and treatable risk factors. However, an earlier age of diabetes diagnosis and longer duration of diabetes characterized those with ESRD. These findings suggest that a failure to meet current standards of diabetes care interacting with an age-related survival benefit contribute to the disproportionate burden of ESRD among FN and possibly other Indigenous peoples.
doi:10.1186/1471-2369-13-57
PMCID: PMC3438064  PMID: 22776036
Indigenous peoples; Aboriginal; First Nations; Diabetes; Chronic kidney disease; End stage renal disease; Risk factors.
4.  Race differences in prevalence of chronic kidney disease among young adults using creatinine-based glomerular filtration rate-estimating equations 
Nephrology Dialysis Transplantation  2010;25(12):3934-3939.
Background. Despite a higher incidence of end-stage renal disease (stage 5), blacks have been shown to have the same or lower prevalence of chronic kidney disease (CKD stages 3 and 4). Current creatinine-based glomerular filtration rate (GFR)-estimating equations may misclassify young, healthy blacks.
Methods. Among 3501 young adults (mean age 45), we compared the prevalence of CKD in blacks and whites using the Modification of Diet in Renal Disease (MDRD) and the CKD Epidemiology Collaboration (CKD-EPI) equations. In addition, we used measured creatinine excretion rates to determine the actual excretion ratio for CARDIA (race coefficient 12%) and applied this to the CKD-EPI equation. We also studied the prevalence of CKD risk factors among black and white participants near the CKD threshold cut-off (eGFR CKD-EPI 60–80 mL/min/1.73 m2) to estimate the relative likelihood of misclassification in blacks and whites.
Results. Using the MDRD equation, prevalence of CKD stages 4 and 5 was higher for blacks compared with whites (0.6% vs. 0.1%, P-value 0.05). In contrast, prevalence of eGFR <60 mL/min/1.73 m2 was significantly higher for whites (3.6%) compared with blacks (1.9%), due to higher prevalence of stage 3 among whites. Prevalence of CKD was similar for blacks and whites using CKD-EPI equation (1.2%), but was higher among blacks when using the CARDIA-derived race coefficient (1.6% vs.1.2%, P-value = 0.03). Among persons with eGFR by CKD-EPI of 60–80 mL/min/1.73 m2, blacks had higher levels of albuminuria, uric acid, systolic blood pressure and higher diabetes prevalence.
Conclusions. CKD classification among young blacks is very sensitive to the race coefficients. Despite whites having higher rates of CKD stage 3, blacks with eGFRs just above the CKD threshold had higher rates of CKD risk factors. Current equations used to define CKD may systematically miss a high-risk group of blacks at a time in the disease course when interventions are crucial.
doi:10.1093/ndt/gfq299
PMCID: PMC3108366  PMID: 20519233
chronic kidney disease; glomerular filtration rate; race
5.  Low documentation of chronic kidney disease among high-risk patients in a managed care population: a retrospective cohort study 
BMC Nephrology  2009;10:25.
Background
Early detection of chronic kidney disease (CKD) is sub-optimal among the general population and among high risk patients. The prevalence and impact of major CKD risk factors, diabetes (DM) and hypertension (HTN), on CKD documentation among managed care populations have not been previously reported. We examined this issue in a Kaiser Permanente Georgia (KPG) CKD cohort.
Methods
KPG enrollees were included in the CKD cohort if they had eGFRs between 60 and 365 days apart that were <90 ml/min during 1999-2006. The current analysis is restricted to participants with eGFR 10-59 ml/min/1.73 m2. CKD documentation was defined as a presenting diagnosis of CKD by a primary care physician or nephrologist using ICD-9 event codes. The association between CKD documentation and DM and HTN were assessed with multivariate logistic regression models.
Results
Of the 50,438 subjects within the overall KPG CKD cohort, 20% (N = 10,266) were eligible for inclusion in the current analysis. Overall, CKD diagnosis documentation was low; only 14.4% of subjects had an event-based CKD diagnosis at baseline. Gender and types 2 diabetes interacted on CKD documentation. The prevalence of CKD documentation increased with the presence of hypertension and/or type 2 diabetes, but type 2 diabetes had a lower effect on CKD documentation. In multivariate analysis, significant predictors of CKD documentation were eGFR, hypertension, type 2 diabetes, congestive heart failure, peripheral artery disease, statin use, age and gender. CKD documentation was lower among women than similarly affected men.
Conclusion
Among patients with an eGFR 10-59, documentation of CKD diagnosis by primary and subspecialty providers is low within a managed care patient cohort. Gender disparities in CKD documentation observed in the general population were also present among KPG CKD enrollees.
doi:10.1186/1471-2369-10-25
PMCID: PMC2753574  PMID: 19758452
6.  Evaluation of cardiovascular disease burden and therapeutic goal attainment in US adults with chronic kidney disease: an analysis of national health and nutritional examination survey data, 2001–2010 
BMC Nephrology  2013;14:132.
Background
For chronic kidney disease (CKD) patients, national treatment guidelines recommend a low-density lipoprotein cholesterol (LDL-C) goal <100 mg/dL and blood pressure (BP) target <130/80 mmHg. This analysis assessed the current status of cardiovascular (CV) risk factor treatment and control in US adults with CKD.
Methods
Weighted prevalence estimates of CV-related comorbidities, utilization of lipid- and BP-lowering agents, and LDL-C and BP goal attainment in US adults with CKD were assessed among 9,915 men and nonpregnant women aged ≥20 years identified from the fasting subsample of the 2001–2010 National Health and Nutritional Examination Survey (NHANES). Analyses were performed using SAS survey procedures that consider the complex, multistage, probability sampling design of NHANES. All estimates were standardized to the 2008 US adult population (≥20 years). Data were stratified by CKD stage based on presence of albuminuria and estimated glomerular filtration rate (eGFR), calculated using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. Stage 3 CKD was subdivided into 3a (eGFR 45–59 mL/min/1.73 m2) and 3b (eGFR 30–44 mL/min/1.73 m2); Stage 5 CKD and dialysis recipients were excluded.
Results
Of the 9,915 NHANES participants identified for analysis, 1,428 had CKD (Stage 1–4), corresponding to a prevalence estimate for US adults aged ≥20 years of 10.2%. Prevalence of CV-related comorbidities increased markedly with CKD stage, with a ~6–12-fold increase in cardiovascular disease, coronary heart disease (CHD), stroke and congestive heart failure between CKD Stage 1 and 4; prevalence of diabetes, hyperlipidemia and hypertension increased by ~1.2–1.6-fold. Use of lipid-lowering agents increased with CKD stage, from 18.1% (Stage 1) to 44.8% (Stage 4). LDL-C goal attainment increased from 35.8% (Stage 1) to 52.8% (Stage 3b), but decreased in Stage 4 (50.7%). BP goal attainment decreased between Stage 1 and 4 (from 49.5% to 30.2%), despite increased use of antihypertensives (from 30.2% to 78.9%).
Conclusions
Individuals with CKD have a high prevalence of CV-related comorbidities. However, attainment of LDL-C or BP goals was low regardless of disease stage. These findings highlight the potential for intensive risk factor modification to maximize CV event reduction in CKD patients at high risk for CHD.
doi:10.1186/1471-2369-14-132
PMCID: PMC3701605  PMID: 23802885
Chronic Kidney Disease; Low-density Lipoprotein Cholesterol; Blood Pressure; Cardiovascular Risk Factors; Goal Attainment
7.  Lower Urinary Connective Tissue Growth Factor Levels and Incident CKD Stage 3 in the General Population 
Background
Connective tissue growth factor (CTGF) is involved in the development and progression of kidney diseases including diabetic nephropathy and kidney fibrosis, but may also play a role in mesangial repair following injury. It is unknown whether, in the general population, urinary CTGF levels are associated with reduction of estimated glomerular filtration rate (eGFR) to less than 60 ml/min/1.73m2 (ie, development of chronic kidney disease [CKD] stage 3).
Study Design
Nested case-control.
Setting & Participants
100 cases of incident CKD stage 3 and 100 age-and sex-matched controls in the Framingham Heart Study (FHS); 141 cases and 135 age-, sexand race-matched controls in the Atherosclerosis Risk in Communities (ARIC) Study. Controls had eGFR ≥60 ml/min/1.73m2 at follow-up in both studies.
Predictors
Urinary CTGF concentrations.
Outcomes
Incident CKD stage 3, defined as eGFR <60 ml/min/1.73m2.
Measurements
Stored urine samples from Framingham Heart Study and ARIC were measured for CTGF. Covariates were obtained from Framingham Heart Study and ARIC participant examinations.
Results
In Framingham Heart Study, the median baseline urinary CTGF concentration was lower among cases (1.35 ng/mL) than controls (2.35 ng/mL; paired t-test P<0.0001). The multivariable-adjusted OR for incident CKD stage 3 was 0.33 (95% confidence interval [CI] 0.17–0.64; P<0.001) per 1-standard deviation increase in log urinary CTGF after adjustment for CKD risk factors, baseline eGFR and baseline log urinary albumin-creatinine ratio, with similar results among participants without diabetes (n=184). Results were not materially different when urinary CTGF was indexed to urinary creatinine (multivariable-adjusted OR, 0.34; 95% CI, 0.21–0.56; P<0.001). A similar, but non-significant, trend of risk of incident CKD stage 3 with lower baseline urinary CTGF concentration was observed in an independent case-control study conducted in the ARIC Study, with the strongest results observed among participants free of diabetes. This inverse relationship was robust in meta-analysis of both the overall and diabetes-free groups.
Limitations
Observational study; causality cannot be inferred.
Conclusions
Lower urinary CTGF concentrations precede the onset of CKD stage 3 in the general population. Further work is required to fully characterize how CTGF influences risk of CKD.
doi:10.1053/j.ajkd.2010.11.022
PMCID: PMC3100386  PMID: 21292366
8.  High Prevalence of Stage 3 Chronic Kidney Disease in Older Adults Despite Normal Serum Creatinine 
BACKGROUND
Serum creatinine is commonly used to diagnose chronic kidney disease (CKD), but may underestimate CKD in older adults when compared with using glomerular filtration rates (eGFR). The magnitude of this underestimation is not clearly defined.
OBJECTIVE
Using the Modification of Diet in Renal Disease (MDRD) equation, to describe both the prevalence and the magnitude of underestimation of stage 3 CKD (GFR 30–59 ml/min/1.73 m2), as well as ideal serum creatinine cutoff values to diagnose stage 3 CKD among Americans ≥65 years of age.
DESIGN
Cross-sectional.
PARTICIPANTS
A total of 3,406 participants ≥65 years of age from the 1999–2004 National Health and Nutrition Examination Surveys (NHANES).
MEASUREMENTS
Serum creatinine levels were used to determine eGFR from the MDRD equation. Information on clinical conditions was self-reported.
RESULTS
Overall, 36.1% of older adults in the US have stage 3 or greater CKD as defined by eGFR values. Among older adults with stage 3 CKD, 80.6% had creatinine values ≤1.5 mg/dl, and 38.6% had creatinine values ≤1.2 mg/dl. Optimal cutoff values for serum creatinine in the diagnosis of stage 3 CKD in older adults were ≥1.3 mg/dl for men and ≥1.0 mg/dl for women, regardless of the presence or absence of hypertension, diabetes, or congestive heart failure.
CONCLUSION
Use of serum creatinine underestimates the presence of advanced (stage 3 or greater) CKD among older adults in the US. Automated eGFR reporting may improve the accuracy of risk stratification for older adults with CKD.
doi:10.1007/s11606-008-0850-3
PMCID: PMC2607515  PMID: 18987917
chronic kidney disease; serum creatinine; older adults; glomerular filtration rate
9.  Correlates of insulin resistance in older individuals with and without kidney disease 
Nephrology Dialysis Transplantation  2011;26(9):2814-2819.
Background. Chronic kidney disease (CKD) is associated with insulin resistance (IR). Prior studies have found that in individuals with CKD, leptin is associated with fat mass but resistin is not and the associations with adiponectin are conflicting. This suggests that the mechanism and factors associated with IR in CKD may differ.
Methods. Of the 2418 individuals without reported diabetes at baseline, participating in the Health, Aging and Body Composition study, a study in older individuals aged 70–79 years, 15.6% had CKD defined as an estimated glomerular filtration rate (eGFR) <60 mL/min/1.73m2 based on cystatin C. IR was defined as the upper quartile of the homeostasis model assessment. The association of visceral and subcutaneous abdominal fat, percent body fat, muscle fat, lipids, inflammatory markers and adiponectin were tested with logistic regression. Interactions were checked to assess whether the factors associated with IR were different in those with and without CKD.
Results. Individuals with IR had a lower eGFR (80.7 ± 20.9 versus 75.6 ± 19.6, P < 0.001). After multivariable adjustment, eGFR (odds ratio per 10 mL/min/1.73m2 0.92, 95% confidence interval 0.87–0.98) and CKD (1.41, 1.04–1.92) remained independently associated with IR. In individuals with and without CKD, the significant predictors of IR were male sex, black race, higher visceral fat, abdominal subcutaneous fat and triglycerides. In individuals without CKD, IR was associated with lower high-density lipoprotein and current nonsmoking status in multivariate analysis. In contrast, among individuals with CKD, interleukin-6 (IL-6) was independently associated with IR. There was a significant interaction of eGFR with race and IL-6 with a trend for adionectin but no significant interactions with CKD (P > 0.1). In the fully adjusted model, there was a trend for an interaction with adiponectin for eGFR (P = 0.08) and significant for CKD (P = 0.04 ), where adiponectin was associated with IR in those without CKD but not in those with CKD.
Conclusions. In mainly Stage 3 CKD, kidney function is associated with IR; except for adiponectin, the correlates of IR are similar in those with and without CKD.
doi:10.1093/ndt/gfq817
PMCID: PMC3203409  PMID: 21248294
chronic kidney disease; cystatin C; insulin resistance; subcutaneous fat
10.  Performance of a Genetic Risk Score for CKD Stage 3 in the General Population 
Background
Recent genome-wide association studies have identified multiple genetic loci that increase the risk of chronic kidney disease (CKD) in the general population. We hypothesized that knowledge of these loci might permit improved CKD risk prediction beyond that provided by traditional phenotypic risk factors.
Study design
Observational cohort study
Setting and participants
Participants who attended the 15th (1977–1979) and 24th (1995–1998) examination cycles of the Original cohort or the 6th (1995–1998) and 8th cycles (2005–2008) of the Offspring cohort of the Framingham Heart Study (n=2,489).
Predictors
Single-nucleotide polymorphisms (SNPs) at 16 stage 3 CKD loci were genotyped and used to construct a genetic risk score. Standard clinical predictors of incident stage 3 CKD were also used.
Outcomes and Measurements
Incident stage 3 CKD was defined as eGFR <60 mL/min/1.73m2 at follow-up. Participants with baseline stage 3 CKD were excluded. Logistic regression was used to generate C statistics, which measured the power of the genetic risk score to discriminate risk of incident CKD stage 3 with and without traditional risk factors.
Results
There were 270 new stage 3 CKD cases during an average of 10.8 years follow-up. The mean (±SD) genetic risk score was 17.5±2.8 among those who developed stage 3 CKD and 17.3±2.6 among those who did not (P-value for genotype score difference=0.2). The odds ratio for stage 3 CKD was 1.06 (95% CI, 1.01–1.11; p=0.03) per additional risk allele, adjusting for age and sex. In the age and sex-adjusted model, the C statistic was 0.748 without the genotype score and 0.751 with the score (P-value for difference=0.3). The risk score was not statistically significant in a multivariable model adjusted for standard stage 3 CKD risk factors (p=0.07).
Limitations
Participants all of European ancestry; genotype score may not be valid in different ancestral groups.
Conclusions
A genetic score generated from 16 known CKD risk alleles did not predict new cases of stage 3 CKD in the community beyond knowledge of common, clinical risk factors alone.
doi:10.1053/j.ajkd.2011.08.030
PMCID: PMC3242901  PMID: 21995970
11.  Estimated GFR and Incident Cardiovascular Disease Events in American Indians: The Strong Heart Study 
Background
In populations with high prevalence of diabetes and obesity, estimating glomerular filtration rate (GFR) by using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation may predict cardiovascular disease risk better than by using the Modification of Diet in Renal Disease (MDRD) Study equation.
Study design
Longitudinal cohort study comparing the association of GFR estimated using either the CKD-EPI or MDRD Study equations with incident cardiovascular disease outcomes.
Setting and participants
American Indians participating in the Strong Heart Study, a longitudinal population-based cohort with high prevalences of diabetes, cardiovascular disease, and CKD.
Predictor or factor
eGFR predicted using the CKD-EPI and MDRD Study equations.
Outcomes
Fatal and nonfatal cardiovascular events, consisting of coronary heart disease, stroke, and heart failure.
Measurements
The association between eGFR and outcomes was explored in Cox proportional hazards models, adjusted for traditional risk factors and albuminuria; the net reclassification index and integrated discrimination improvement were determined for the CKD-EPI versus MDRD Study equations.
Results
Among 4549 participants, diabetes was present in 45%, cardiovascular disease in 7%, and stage 3–5 CKD in 10%. Over a median of 15 years, there were 1280 cases of incident CVD, 929 of incident coronary heart disease, 305 of incident stroke, and 381 of incident heart failure. Reduced eGFR (<90 mL/min/1.73 m2) was associated with adverse events in most models. Compared with the MDRD Study equation, the CKD-EPI equation correctly reclassified 17.0% of 2,151 participants without incident CVD to a lower risk (higher eGFR) category and 1.3% (n=28) were incorrectly reclassified to a higher risk (lower eGFR) category.
Limitations
Single measurements of eGFR and albuminuria at study visits.
Conclusions
Although eGFR based on either equation had similar associations with incident cardiovascular disease, coronary heart disease, stroke, and heart failure events, among those not having events, reclassification of participants to eGFR categories was superior using the CKD-EPI equation compared with the MDRD Study equation.
doi:10.1053/j.ajkd.2012.06.015
PMCID: PMC3473098  PMID: 22841159
cardiovascular disease risk; chronic kidney disease; estimated glomerular filtration rate; Strong Heart Study
12.  Association of Chronic Kidney Disease with Atrial Fibrillation Among Adults in the United States: Reasons for Geographic and Racial Differences in Stroke (REGARDS) Study 
Background
Atrial fibrillation (AF) is common among patients with end-stage renal disease, but few data are available on its prevalence among adults with chronic kidney disease (CKD) of lesser severity.
Methods and Results
We evaluated the association of CKD with electrocardiogram-detected AF among 26,917 participants in the REasons for Geographic and Racial Differences in Stroke (REGARDS) study, a population-based cohort of African-American and white US adults ≥45 years of age. Estimated glomerular filtration rate (eGFR) was calculated using the abbreviated Modification of Diet in Renal Disease study equation and albuminuria was defined as a urinary albumin to creatinine ratio ≥30 mg/g. Participants were categorized by renal function: no CKD (eGFR ≥60 ml/min/1.73m2 without albuminuria, n=21,081), stage 1–2 CKD (eGFR ≥60 ml/min/1.73m2 with albuminuria n=2,938), stage 3 CKD (eGFR 30 to 59 ml/min/1.73m2, n=2,683) and stage 4–5 CKD (eGFR <30 ml/min/1.73m2, n=215). The prevalence of AF among participants without CKD, and with stage 1–2, stage 3, and stage 4–5 CKD was 1.0%, 2.8%, 2.7% and 4.2%, respectively. Compared to participants without CKD, the age, race, sex adjusted odds ratios for prevalent AF were 2.67 (95% CI 2.04 – 3.48), 1.68 (95% CI 1.26 – 2.24) and 3.52 (95% CI 1.73–7.15) among those with stage 1–2, stage 3 and stage 4–5 CKD. The association between CKD and prevalent AF remained statistically significant after further multivariable adjustment and was consistent across numerous subgroups.
Conclusions
- Regardless of severity, CKD is associated with an increased prevalence of AF among US adults.
doi:10.1161/CIRCEP.110.957100
PMCID: PMC3049935  PMID: 21076159
chronic kidney disease; atrial fibrillation; electrocardiography
13.  Impact of non-dialysis chronic kidney disease on survival in patients with septic shock 
BMC Nephrology  2013;14:77.
Background
Chronic kidney disease (CKD) is known to expose the patient to a high risk of death due to cardiovascular and infective causes. In parallel, septic shock is a major challenge for cardiovascular and immune system. Therefore we tried to determine whether non-dialysis CKD, defined as a baseline estimated glomerular filtration rate (eGFR) <60ml/min/1.73m2, for three months prior to the onset of septic shock is an independent risk factor for death.
Methods
All patients treated in a teaching hospital medical ICU for septic shock between January 2007 and December 2009 were retrospectively analyzed. Patients in whom baseline eGFR could not be determined (n=14) or patients treated by chronic dialysis (n=21) or kidney transplantation (n=14) were excluded. A total of 163 patients were included. The population was divided according to baseline eGFR ≥ 60ml/min/1.73m2 (non-CKD group, n=107) and < 60ml/min/1.73m2 (CKD group, n=56). Twenty-eight-day and 1-year survival curves were plotted. Prognostic factors were determined using Cox proportional hazards models.
Results
Baseline eGFR was significantly higher in the non-CKD group than in the CKD group (81 (67–108) vs. 36 (28–44) ml/min/1.73m2, respectively; p=0.001). Age, SAPS II, serum creatinine on admission and the number of patients with a history of diabetes, hypertension, heart failure, peripheral artery disease, coronary artery disease and statin medication were significantly higher in the CKD group than in the non-CKD group. The mortality rate was lower in the non-CKD group than in the CKD group after 28 days (50% vs. 70%, respectively; p=0.03) and 1 year (64% vs. 82%, respectively; p=0.03). On multivariate analysis, the dichotomous variable CKD (eGFR < 60ml/min/1.73m2) remained significantly associated with the 28-day and 1-year mortality.
Conclusions
Non-dialysis CKD appears to be an independent risk factor for death after septic shock.
doi:10.1186/1471-2369-14-77
PMCID: PMC3623660  PMID: 23548034
14.  Comparison of risk prediction using the CKD-EPI equation and the MDRD Study equation for estimated glomerular filtration rate 
JAMA : the journal of the American Medical Association  2012;307(18):10.1001/jama.2012.3954.
Context
The CKD-EPI equation more accurately estimates glomerular filtration rate (eGFR) than the MDRD Study equation using the same variables, especially at higher GFR, but definitive evidence of its risk implications in diverse settings is lacking.
Objective
To evaluate risk implications of eGFRCKD-EPI compared to eGFRMDRD in populations with a broad range of demographic and clinical characteristics.
Design, Setting, and Participants
Meta-analyses based on data from 1,130,472 adults (aged 18 years or older) from 25 general population, 7 high-risk (of vascular disease), and 13 chronic kidney disease (CKD) cohorts. Data transfer and analyses were conducted between March 2011 and March 2012.
Main Outcome Measures
All-cause mortality (84,482 deaths from 40 cohorts), cardiovascular mortality (22,176 events from 28 cohorts), and end-stage renal disease (ESRD) (7,644 events from 21 cohorts) during 9.4 million person-years of follow-up (median of mean follow-up time across cohorts was 7.4 years).
Results
eGFR was classified into six categories (≥90, 60-89, 45-59, 30-44, 15-29, and <15 ml/min/1.73m2) by both equations. Compared to eGFRMDRD, 24.4% and 0.6% of participants from general population cohorts were reclassified to a higher and lower eGFR category by the CKD-EPI equation, respectively, and the prevalence of CKD stage 3-5 (eGFR <60 ml/min/1.73m2) was reduced from 8.7% to 6.3%. 34.7% of participants with eGFRMDRD 45-59 were reclassified to eGFRCKD-EPI 60-89 and had lower incidence rates (per 1,000 person-years) of outcomes compared to those not reclassified (9.9 vs. 34.5 for all-cause mortality, 2.7 vs. 13.0 for cardiovascular mortality, and 0.5 vs. 0.8 for ESRD). The corresponding adjusted hazard ratios were 0.80 (95% confidence interval, 0.74 to 0.86) for all-cause mortality, 0.73 (0.65 to 0.82) for cardiovascular mortality, and 0.49 (0.27 to 0.88) for ESRD. Similar findings were observed in other eGFRMDRD categories. Net reclassification improvement (NRI) based on eGFR categories was significantly positive for all outcomes (range from 0.06 to 0.13, all P<0.001). NRI was similarly positive in most subgroups defined by age (< and ≥65 years), sex, race/ethnicity (white, Asian, and black), and presence or absence of diabetes and hypertension. The results in high-risk and CKD cohorts were largely consistent with the general population cohorts.
Conclusions
The CKD-EPI equation classified fewer individuals as CKD and more accurately categorized the risk for mortality and ESRD than did the MDRD Study equation across a broad range of populations.
doi:10.1001/jama.2012.3954
PMCID: PMC3837430  PMID: 22570462
15.  A comparison of estimated glomerular filtration rates using Cockcroft−Gault and the Chronic Kidney Disease Epidemiology Collaboration estimating equations in HIV infection 
HIV Medicine  2013;15(3):144-152.
Objectives
The aim of this study was to determine whether the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)- or Cockcroft−Gault (CG)-based estimated glomerular filtration rates (eGFRs) performs better in the cohort setting for predicting moderate/advanced chronic kidney disease (CKD) or end-stage renal disease (ESRD).
Methods
A total of 9521 persons in the EuroSIDA study contributed 133 873 eGFRs. Poisson regression was used to model the incidence of moderate and advanced CKD (confirmed eGFR < 60 and < 30 mL/min/1.73 m2, respectively) or ESRD (fatal/nonfatal) using CG and CKD-EPI eGFRs.
Results
Of 133 873 eGFR values, the ratio of CG to CKD-EPI was ≥ 1.1 in 22 092 (16.5%) and the difference between them (CG minus CKD-EPI) was ≥ 10 mL/min/1.73 m2 in 20 867 (15.6%). Differences between CKD-EPI and CG were much greater when CG was not standardized for body surface area (BSA). A total of 403 persons developed moderate CKD using CG [incidence 8.9/1000 person-years of follow-up (PYFU); 95% confidence interval (CI) 8.0–9.8] and 364 using CKD-EPI (incidence 7.3/1000 PYFU; 95% CI 6.5–8.0). CG-derived eGFRs were equal to CKD-EPI-derived eGFRs at predicting ESRD (n = 36) and death (n = 565), as measured by the Akaike information criterion. CG-based moderate and advanced CKDs were associated with ESRD [adjusted incidence rate ratio (aIRR) 7.17; 95% CI 2.65–19.36 and aIRR 23.46; 95% CI 8.54–64.48, respectively], as were CKD-EPI-based moderate and advanced CKDs (aIRR 12.41; 95% CI 4.74–32.51 and aIRR 12.44; 95% CI 4.83–32.03, respectively).
Conclusions
Differences between eGFRs using CG adjusted for BSA or CKD-EPI were modest. In the absence of a gold standard, the two formulae predicted clinical outcomes with equal precision and can be used to estimate GFR in HIV-positive persons.
doi:10.1111/hiv.12095
PMCID: PMC4228765  PMID: 24118916
chronic kidney disease; end stage renal disease; eGFR; renal function
16.  Retinal Arteriolar Narrowing and Subsequent Development of CKD Stage 3: The Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Microvascular disease is a major pathogenic factor for chronic kidney disease (CKD) in persons with diabetes, but the role of microvascular disease in the development of CKD in the general population is unclear. The aim of this study is to examine whether microvascular disease precedes the development of CKD stage 3 in participants of the Multi-Ethnic Study of Atherosclerosis (MESA).
Study Design
Population-based cohort study.
Setting & Participants
MESA is a prospective cohort study of adults aged 45-84 years living in 6 US communities; 4,594 adults with estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 when they underwent retinal photography (visit 2: in 2002-2004) were examined.
Predictor
Retinal microvascular caliber measured from fundus photographs.
Outcomes
Incident CKD stage 3 (ie, eGFR <60 mL/min/1.73 m2) at 2 subsequent follow-up examinations (visit 3 in 2004-2005, and visit 4 in 2005-2007) and an annual eGFR decrease >1 mL/min/1.73 m2 computed using the CKD Epidemiology Collaboration (CKD-EPI) equation.
Results
After a median follow-up of 4.8 years, there were 232 incident CKD stage 3 cases. Overall, retinal microvascular caliber was not associated with incident CKD stage 3. However, in race-stratified analysis, narrower arterioles in whites was associated with a higher risk of developing CKD stage 3 after adjusting for age, sex, blood pressure, diabetes, and other factors (HR, 1.78; 95% CI, 1.01-3.15; P = 0.04, lowest vs highest arteriolar caliber tertile). This association was seen even in whites without hypertension and diabetes (HR, 2.95; 95% CI, 1.10-7.98; P = 0.03). Retinal arteriolar caliber was not associated with incident CKD stage 3 in African Americans, Chinese, or Hispanics.
Limitations
Analyses were based on a single eGFR measurement, and retinal microvascular caliber and eGFR measurements were not ascertained concurrently.
Conclusion
Microvascular changes as manifest in the eye may contribute to the development of CKD stage 3 in whites.
doi:10.1053/j.ajkd.2011.02.382
PMCID: PMC3197818  PMID: 21549464
Microvascular changes; retinal microvascular caliber; chronic kidney disease
17.  Association of eGFR-Related Loci Identified by GWAS with Incident CKD and ESRD 
PLoS Genetics  2011;7(9):e1002292.
Family studies suggest a genetic component to the etiology of chronic kidney disease (CKD) and end stage renal disease (ESRD). Previously, we identified 16 loci for eGFR in genome-wide association studies, but the associations of these single nucleotide polymorphisms (SNPs) for incident CKD or ESRD are unknown. We thus investigated the association of these loci with incident CKD in 26,308 individuals of European ancestry free of CKD at baseline drawn from eight population-based cohorts followed for a median of 7.2 years (including 2,122 incident CKD cases defined as eGFR <60ml/min/1.73m2 at follow-up) and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). SNPs at 11 of the 16 loci (UMOD, PRKAG2, ANXA9, DAB2, SHROOM3, DACH1, STC1, SLC34A1, ALMS1/NAT8, UBE2Q2, and GCKR) were associated with incident CKD; p-values ranged from p = 4.1e-9 in UMOD to p = 0.03 in GCKR. After adjusting for baseline eGFR, six of these loci remained significantly associated with incident CKD (UMOD, PRKAG2, ANXA9, DAB2, DACH1, and STC1). SNPs in UMOD (OR = 0.92, p = 0.04) and GCKR (OR = 0.93, p = 0.03) were nominally associated with ESRD. In summary, the majority of eGFR-related loci are either associated or show a strong trend towards association with incident CKD, but have modest associations with ESRD in individuals of European descent. Additional work is required to characterize the association of genetic determinants of CKD and ESRD at different stages of disease progression.
Author Summary
Chronic kidney disease (CKD) affects about 6%–11% of the general population, and progression to end stage renal disease (ESRD) has a significant public health impact. Family studies suggest that the risk for CKD and ESRD is heritable. Unraveling the genetic underpinning of risk for these diseases may lead to the identification of novel mechanisms and thus diagnostic and therapeutic tools. We have previously identified 16 genetic markers in association with kidney function and prevalent CKD in general population studies. However, little is known about the relevance of these SNPs to the initial development of CKD or to ESRD risk. Therefore, we have now analyzed the association of these markers with the initiation of CKD in more than 26,000 individuals from the general population using serial estimations of kidney function, and with ESRD in four case-control studies in subjects of European ancestry (3,775 cases, 4,577 controls). We show that many of the 16 markers are also associated or show a strong trend towards association with initiation of CKD, while only 2 markers are nominally associated with ESRD. Further work is required to characterize the association of genetic determinants of different stages of CKD progression.
doi:10.1371/journal.pgen.1002292
PMCID: PMC3183079  PMID: 21980298
18.  Prevalence, determinants, and management of chronic kidney disease in Karachi, Pakistan - a community based cross-sectional study 
BMC Nephrology  2014;15:90.
Background
Chronic kidney disease (CKD) is increasing being recognized as a global public health problem. However, there is dearth of information on the prevalence, determinants, and management of CKD from low- and middle-income countries. The objectives of the study were to determine the 1) prevalence of CKD; 2) socio-demographic and clinical factors associated with CKD; and 3) the existing management of these patients with regards to blood pressure control, and use of antihypertensive medications.
Methods
We conducted a cross-sectional study on 2873 participants aged ≥40 years in 12 representative communities in Karachi, Pakistan. The primary outcome was clinically significant CKD defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 estimated by CKD-EPI (CKD Epidemiology Collaboration) Pakistan equation (0.686 × CKD-EPI1.059) or urinary albumin to creatinine ratio ≥3 mg/mmol (i.e. KDOQI CKD stage G3, A2 or worse).
Results
The overall prevalence (95% CI) of CKD was 12.5% (11.4 – 13.8%). The factors independently associated with CKD were older age, hypertension, diabetes, elevated systolic blood pressure, raised fasting plasma glucose, raised triglycerides, and history of stroke (p < 0.05 for each). About 267 (74.4%, 69.5 – 78.8%) adults with CKD had concomitant hypertension. Of these, 130 (48.7%, 42.6 – 54.9%) were on antihypertensive medications, and less than 20% had their BP controlled to conventional target of ≤140/90 mm Hg, and only 16.9% (12.6 – 21.9%) were on blockers of renin-angiotensin system alone or in combination with other drugs.
Conclusions
Clinically significant CKD is common among Pakistani adults. The conventional risk factors for CKD and poor control of blood pressure among patients with CKD highlight the need to integrate CKD prevention and management in the primary care infrastructure in Pakistan, and possibly neighbouring countries.
doi:10.1186/1471-2369-15-90
PMCID: PMC4065316  PMID: 24927636
Albuminuria; Chronic kidney disease; CKD-EPI Pakistan; Glomerular filtration rate; South Asians
19.  Estimated GFR reporting is not sufficient to allow detection of chronic kidney disease in an Italian regional hospital 
BMC Nephrology  2009;10:24.
Background
Chronic kidney disease (CKD) is an emerging worldwide problem. The lack of attention paid to kidney disease is well known and has been described in previous publications. However, little is known about the magnitude of the problem in highly specialized hospitals where serum creatinine values are used to estimate GFR values.
Methods
We performed a cross-sectional evaluation of hospitalized adult patients who were admitted to the medical or surgical department of Santa Maria della Misericordia Hospital in 2007. Information regarding admissions was derived from a database. Our goal was to assess the prevalence of CKD (defined as an estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2) and detection of CKD using diagnostic codes (Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM]). To reduce the impact of acute renal failure on the study, the last eGFR obtained during hospitalization was the value used for analysis, and intensive care and nephrology unit admissions were excluded. We also excluded patients who had ICD-9-CM codes for renal replacement therapy, acute renal failure, and contrast administration listed as discharge diagnoses.
Results
Of the 18,412 patients included in the study, 4,748 (25.8%) had reduced eGFRs, falling into the category of Kidney Disease Outcomes Quality Initiative (KDOQI) stage 3 (or higher) CKD. However, the diagnosis of CKD was only reported in 19% of these patients (904/4,748). It is therefore evident that there was a "gray area" corresponding to stage 3 CKD (eGFR 30-59 ml/min), in which most CKD diagnoses are missed. The ICD-9 code sensitivity for detecting CKD was significantly higher in patients with diabetes, hypertension, and cardiovascular disease (26.8%, 22.2%, and 23.7%, respectively) than in subjects without diabetes, hypertension, or cardiovascular disease (p < 0.001), but these values are low when the widely described relationship between such comorbidities and CKD is considered.
Conclusion
Although CKD was common in this patient population at a large inpatient regional hospital, the low rates of CKD detection emphasize the primary role nephrologists must play in continued medical education, and the need for ongoing efforts to train physicians (particularly primary care providers) regarding eGFR interpretation and systematic screening for CKD in high-risk patients (i.e., the elderly, diabetics, hypertensives, and patients with CV disease).
doi:10.1186/1471-2369-10-24
PMCID: PMC2749028  PMID: 19723333
20.  Associations of Urinary Levels of Kidney Injury Molecule-1 (KIM-1) and Neutrophil Gelatinase-Associated Lipocalin (NGAL) With Kidney Function Decline in the Multi-Ethnic Study of Atherosclerosis (MESA) 
Background
Whether elevations of urinary biomarkers of tubular injury (urine neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1)) are associated with future risk of kidney disease has not been investigated.
Study Design
1:1 nested case-control study
Setting & Participants
686 participants in the Multi-Ethnic Study of Atherosclerosis (MESA).
Predictor
NGAL and KIM-1 were measured at baseline and expressed as log-transformed continuous variables and categorized into deciles.
Outcomes
Kidney function was estimated by cystatin C using the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equation. Incident CKD Stage 3 was defined as eGFR <60 ml/min/1.73m2 and a eGFR decline >1 ml/min/1.73m2 per year, and rapid kidney function decline (RKFD) was defined as decline of ≥3 ml/min/1.73m2 per year.
Measurements
Cases were defined as persons with eGFR >60 ml/min/1.73m2 who subsequently developed incident CKD Stage 3 and/or had RKFD by MESA year 5 visit. Controls were matched for age, gender, race, diabetes, and baseline eGFR. We adjusted for age, hypertension and presence of albuminuria (ACR ≥30 mg/g).
Results
Of the 343 cases, 145 had incident CKD Stage 3, 141 had RKFD and 57 had both. Mean eGFR for controls was 81 (±10) ml/min/1.73m2 at baseline and 80 (±10) at follow-up, compared with 82 (±13) and 58 (±10) for cases. Each doubling of KIM-1 (pg/ml) was associated with an OR of 1.15 (95% CI, 1.02-1.29) for incident CKD Stage 3 and/or RKFD. Compared to the lowest 90%, the highest decile of KIM-1 was associated with an OR of 2.02 (95% CI, 1.15-3.56) for the outcome; these associations were independent of albuminuria. NGAL levels (ng/ml) were not associated with incident CKD Stage 3 and/or RKFD (OR, 1.04; 95% CI, 0.99-1.10). Results were similar when KIM-1 and NGAL were standardized for urine creatinine.
Limitations
The case-control design limits ability to account for persons who died or were not available for follow-up.
Conclusions
Urinary KIM-1 is associated with future risk of kidney disease independent of albuminuria. Urinary biomarkers of tubular injury are a promising tool for identifying persons at risk for CKD.
doi:10.1053/j.ajkd.2012.05.014
PMCID: PMC3690926  PMID: 22749388
KIM-1; NGAL; kidney function decline
21.  Chronic Kidney Disease as a Predictor of Cardiovascular Disease (From the Framingham Heart Study) 
Chronic kidney disease (CKD) is a risk factor for cardiovascular disease (CVD), although shared risk factors may mediate much of the association. We related CKD and CVD in the setting of specific CVD risk factors and determined whether more advanced CKD was a CVD risk equivalent. The Framingham Heart Study original cohort (n=2471, mean age 68 years, 58.9% women) was studied. Glomerular filtration rate (eGFR) was estimated using the simplified Modification of Diet in Renal Disease Study equation. CKD was defined as eGFR < 59 mL/min per 1.73 m2 (women) and < 64 (men) and Stage 3b CKD defined as eGFR 30-44 (women) and 30-50 (men). Cox Proportional Hazard models adjusting for CVD risk factors were used to relate CKD to CVD. We tested for effect modification by CVD risk factors. Overall, 23.2% of the study sample had CKD (n=574; mean eGFR 50 mL/min per 1.73 m2) and 5.3% had Stage 3b CKD (n=131; mean eGFR 42 mL/min per 1.73 m2). In multivariable models (mean follow-up time 16 years), Stage 3 CKD was marginally associated with CVD (HR=1.17, 95% CI 0.99-1.38, p=0.06), whereas Stage 3b CKD was associated with CVD [HR=1.41, 95% CI 1.05-1.91, p=0.02]. Upon testing CVD risk equivalency, the risk of CVD for Stage 3b CKD among participants with prior CVD was significantly lower as compared to participants with prior CVD and no Stage 3b CKD (age- and sex-adjusted HR for CVD = 0.66 [95% CI 0.47 to 0.91], p=0.01). Low HDL modified the association between CKD and CVD (p-value=0.004 for interaction). Stage 3b CKD is associated with CVD but is not a CVD risk equivalent. In conclusion, CVD risk in the setting of CKD is higher in the setting of low HDL cholesterol.
doi:10.1016/j.amjcard.2008.02.095
PMCID: PMC2517213  PMID: 18572034
22.  Role of Traditional Risk Factors and Antiretroviral Drugs in the Incidence of Chronic Kidney Disease, ANRS CO3 Aquitaine Cohort, France, 2004–2012 
PLoS ONE  2013;8(6):e66223.
Objective
To examine the role of antiretroviral drugs (ART), HIV-related and traditional risk factors on the incidence of chronic kidney disease (CKD) in HIV-infected patients.
Design
Prospective hospital-based cohort of HIV-infected patients from 2004 to 2012.
Methods
CKD was defined using MDRD equation as an estimated glomerular filtration rate (eGFR) less than 60 ml/mn/1.73 m2 at 2 consecutive measurements ≥3 months apart. Poisson regression models were used to study determinants of CKD either measured at baseline or updated. ART exposure was classified as ever or never. We additionally tested the role of tenofovir (TDF), whether or not prescribed concomitantly with a Protease Inhibitor (PI), taking into account the cumulative exposure to the drug.
Results
4,350 patients (74% men) with baseline eGFR>60 ml/mn/1.73 m2 were followed for a median of 5.8 years. At the end of follow-up, 96% had received ART, one third of them (35%) jointly received TDF and a PI. Average incidence rate of CKD was 0.95% person-years of follow-up. Incidence of CKD was higher among women (IRR = 2.2), older patients (>60 y vs <45 y: IRR = 2.5 and 45–60 y: IRR = 1.7), those with diabetes (IRR = 1.9), high blood pressure (IRR = 1.5), hyperlipidemia (IRR = 1.5), AIDS stage (IRR = 1.4), low baseline eGFR (IRR = 15.8 for 6090 and IRR = 7.1 for 70500/mm3 (IRR = 2.5), and exposure to TDF (IRR = 2.0). Exposure to TDF was even strongly associated with CKD when co-administered with PIs (IRR = 3.1 vs 1.3 when not, p<0,001). A higher risk of CKD was found when tenofovir exposure was >12 months [IRR = 3.0 with joint PIs vs 1.3 without (p<0.001)]. A vast majority of those developing CKD (76.6%) had a baseline eGFR between 60 and 80 ml/mn/1.73 m2.
Conclusion
In patients with eGFR between 60 and 80 mL/min/1.73 m2, a thorough control of CKD risk factors is warranted. The use of TDF, especially when co-administered with PIs, should be mentioned as a relative contraindication in presence of at least one of these risk factors.
doi:10.1371/journal.pone.0066223
PMCID: PMC3680439  PMID: 23776637
23.  Higher Serum Direct Bilirubin Levels Were Associated with a Lower Risk of Incident Chronic Kidney Disease in Middle Aged Korean Men 
PLoS ONE  2014;9(2):e75178.
Background
The association between serum bilirubin levels and incident chronic kidney disease (CKD) in the general population is unknown. We aimed to examine the association between serum bilirubin concentration (total, direct, and indirect) and the risk of incident CKD.
Methods and Findings
Longitudinal cohort study of 12,823 Korean male workers 30 to 59 years old without CKD or proteinuria at baseline participating in medical health checkup program in a large worksite. Study participants were followed for incident CKD from 2002 through 2011. Estimated glomerular filtration rate (eGFR) was estimated by using the CKD-EPI equation. CKD was defined as eGFR <60 mL/min per 1.73 m2. Parametric Cox models and pooled logistic regression models were used to estimate adjusted hazard ratios for incident CKD. We observed 238 incident cases of CKD during 70,515.8 person-years of follow-up. In age-adjusted models, the hazard ratios for CKD comparing quartiles 2–4 vs. quartile 1 of serum direct bilirubin were 0.93 (95% CI 0.67–1.28), 0.88 (0.60–1.27) and 0.60 (0.42–0.88), respectively. In multivariable models, the adjusted hazard ratio for CKD comparing the highest to the lowest quartile of serum direct bilirubin levels was 0.60 (95% CI 0.41–0.87; P trend = 0.01). Neither serum total nor indirect bilirubin levels were significantly associated with the incidence of CKD.
Conclusions
Higher serum direct bilirubin levels were significantly associated with a lower risk of developing CKD, even adjusting for a variety of cardiometabolic parameters. Further research is needed to elucidate the mechanisms underlying this association and to establish the role of serum direct bilirubin as a marker for CKD risk.
doi:10.1371/journal.pone.0075178
PMCID: PMC3930500  PMID: 24586219
24.  Lifetime Incidence of CKD Stages 3–5 in the United States 
Background
Lifetime risk estimates of chronic kidney disease (CKD) can motivate preventative behaviors at the individual level and forecast disease burden and health care utilization at the population level.
Study Design
Markov Monte Carlo model simulation study.
Setting & Population
Current U.S. black and white population.
Model, Perspective, & Timeframe
Markov models simulating kidney disease development, using an individual perspective and lifetime horizon.
Outcomes
Age-, sex- and race-specific residual lifetime risks of CKD stages 3a+ (eGFR<60 ml/min/1.73m2), 3b+ (eGFR<45 ml/min/1.73 m2), and 4+ (eGFR<30 ml/min/1.73m2), and end stage renal disease (ESRD).
Measurements
State transition probabilities of developing CKD and of dying prior to its development were modeled using: 1) mortality rates from National Vital Statistics Report, 2) mortality risk estimates from a 2-million person meta-analysis, and 3) CKD prevalence from National Health and Nutrition Examination Surveys. Incidence, prevalence, and mortality related to ESRD were supplied by the US Renal Disease System.
Results
At birth, the overall lifetime risks of CKD stages 3a+, 3b+, 4+, and ESRD were 59.1%, 33.6%, 11.5%, and 3.6%, respectively. Women experienced greater CKD risk yet lower ESRD risk than men; blacks of both sexes had markedly higher CKD stage 4+ and ESRD risk (lifetime risks for white men, white women, black men, and black women, respectively: 53.6%, 64.9%, 51.8%, and 63.6% [CKD stage 3a+]; 29.0%, 36.7%, 33.7%, and 40.2% [CKD stage 3b+]; 9.3%, 11.4%, 15.8%, and 18.5% [CKD stage 4+]; and 3.3%, 2.2%, 8.5%, and 7.8% [ESRD]). Risk of CKD increased with age, with approximately one-half of CKD stage 3a+ cases developing after 70 years of age.
Limitations
CKD incidence estimates were modeled from prevalence in the U.S. population.
Conclusions
In the U.S., the lifetime risk of developing CKD stage 3a+ is high, underscoring the importance of primary prevention and effective therapy to reduce CKD-related morbidity and mortality.
doi:10.1053/j.ajkd.2013.03.009
PMCID: PMC3723711  PMID: 23566637
25.  Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Kidney Injury Molecule 1 (KIM-1) as Predictors of Incident CKD Stage 3: The Atherosclerosis Risk in Communities (ARIC) Study 
Background
Identifying individuals at risk for chronic kidney disease (CKD) is critical for timely treatment initiation to slow progression of the disease. Neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule 1 (KIM-1) are known biomarkers of acute kidney injury, but it is unknown whether these markers are associated with incident CKD stage 3 in the general population.
Study Design
Matched case-control study
Setting and Participants
African American and Caucasian participants from the Atherosclerosis Risk in Communities (ARIC) study who at baseline had an estimated glomerular filtration rate ≥ 60 ml/min/1.73 m2 and urinary albumin-creatinine ratio (UACR) ≤ 30 mg/g. A total of 143 controls were matched on age, sex and race to 143 cases of incident CKD stage 3 after 8.6 years of follow-up.
Predictors
Quartile of NGAL and KIM-1.
Outcomes & Measurements
Incident CKD stage 3 (eGFR < 60 ml/min/1.73 m2 at follow-up and a decrease in eGFR from baseline to follow-up of ≥25%)
Results
Both NGAL (p=0.05) and KIM-1 (p<0.001) were positively correlated with baseline UACR; neither was associated with baseline eGFR. Participants with NGAL concentrations in the fourth quartile had more than 2-fold higher odds (adjusted OR, 2.11, 95% CI, 0.96–4.64) of incident CKD stage 3 compared to participants in the first quartile after multivariable adjustment (p-trend=0.03). Adjustment for urinary creatinine and albumin resulted in a non-significant association (highest quartile adjusted OR. 1.52; 95% CI, 0.64–3.58; p=0.2). No significant association between KIM-1 levels and incident CKD was observed in crude or adjusted models.
Limitations
The relatively small sample size of the study limits precision and power to detect weak associations.
Conclusions
Higher NGAL levels, but not KIM-1 levels, were associated with incident CKD stage 3. Adjustment for urinary creatinine and albumin concentration attenuated this association. Additional studies are needed to confirm these findings and assess the utility of urinary NGAL as a marker of CKD risk.
doi:10.1053/j.ajkd.2012.02.336
PMCID: PMC3399971  PMID: 22542304

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